The specific forms of AML and MDS in the current study involve deletions on the arm of a specific chromosome in blood cells (del(5q). In patients with less aggressive forms of del(5q) MDS, the percentage of bone marrow blasts in their blood (the earliest, most immature cells of the myeloid cell line) is less than 5 percent. This means treatment prognosis for those patients typically is good, according to the study’s lead investigator, Daniel Starczynowski PhD, a researcher in the division of Experimental Hematology and Cancer Biology, part of the CBDI at Cincinnati Children’s.

“Unfortunately, a large portion of del(5q) AML and MDS patients have increased number of bone marrow blasts and additional chromosomal mutations,” Starczynowski said. “These patients have very poor prognosis because the disease is very resistant to available treatments such as chemotherapy and radiation. Finding new therapies is important and this study identifies new therapeutic possibilities.”

The researchers conducted their study in human AML/MDS cells and mouse models of del(5q) AML/MDS. They found that reduced expression of a certain gene in blood cells (miR-146a) led to activation of a molecular signaling network involving several components of NF-kB, one of which involved a protein called p62 — a critical regulator of cell metabolism, cellular remodeling and certain cancers.

Deletion of the miR-146a gene led to overexpression of p62, which caused sustained activation of what researchers identified as an NF-kB signaling network. This fueled the survival and aggressive growth of leukemic cells in cells and in mouse models.

Earlier attempts in previous studies to directly inhibit NF-kB (a key molecular facilitator to the leukemic process) have not proven successful, according to investigators on the current paper. So the authors performed follow-up laboratory tests to look for possible vulnerabilities to NF-kB and a potential workaround by targeting instead p62 within the NF-kB signaling network.

The researcher next tested inhibiting/knocking down p62 as an experimental treatment strategy in mouse models of leukemia and in human cells. The authors reported that targeting p62 prevented expansion of leukemic cells in mouse models and reduced the number of leukemia cell colonies by 80 percent in human AML/MDS cells.

Starczynowski stressed that significant additional research is needed to further verify the findings and learn more about the molecular processes involved. He also cautioned that laboratory results in mouse models do not necessarily translate to humans, and it isn’t known at this time how the findings might be directly applicable to clinical treatment.

In Norway, no other forms of cancer take as many lives as lung cancer. Each year, 2800 Norwegians develop the dreaded disease. Their prognosis is unpromising: six out of seven die within five years.

What is especially unfortunate about lung cancer is that the tumor has ample space to grow. It can thus grow for a long time before being detected.

Most patients have their first diagnosis made by X-ray imaging. Each year, Oslo University Hospital takes 30 000 chest X-rays. Nationwide, this number exceeds one million.

Nobody has ever investigated how well X-ray images function with a view to detecting lung cancer and other diseases of the chest region.

“X-ray technology has remained nearly unaltered for one hundred years,” says Trond Mogens Aaløkken at the Department of Radiology and Nuclear Medicine, Oslo University Hospital. In cooperation with a group of physicists at the Intervention Centre he has made a comparison of the proportion of patients who obtain a correct diagnosis with X-ray images and how many patients might have obtained a correct diagnosis with computer tomography (CT), which is a far more modern imaging technology.

While X-ray images are two-dimensional, CT images are three-dimensional. CT images can thus reveal the exact location of the tumor.

Too much radiation before

Until today, the radiation dose from examinations of lungs with CT has been one hundred times higher than from regular X-ray examinations. A CT scan is equivalent to five years of natural background radiation.

Radiologists have therefore been reluctant to use CT for an initial diagnosis of lung cancer.

If the X-ray examination is negative, some months may pass before the patient is referred for a CT scan. Then, it may already be too late.

“It’s sad that so many come to be treated too late because the hospitals are reluctant to use CT. The survival rate can be increased significantly if the lung cancer is initially detected by CT,” Aaløkken points out to the research magazine Apollon.

In recent years, CT scanners have become far more effective. The mathematical method for reconstructing pictures has changed completely. This means that the images now contain more information, while the radiation dose has decreased.

Little radiation now

Researchers at the Intervention Centre have now succeeded in producing CT images with the same low radiation dose as a regular X-ray image.

“We still cannot achieve the same high-quality images by replacing standard full-dose CT with ultralow-dose CT, but we have wondered whether the old low-quality X-ray examinations can be replaced by ultralow-dose CT. Although the CT dose is nearly as low as for a chest X-ray, we can obtain far more information from the images,” says associate professor Anne Catrine Trægde Martinsen, who works at the Intervention Centre and the Department of Physics, University of Oslo.

To find out what works best, the researchers have undertaken a pilot study in which they made both X-ray images and ultralow-dose CT images of a small sample of patients for whom the researchers knew the correct answer beforehand.

The radiologists who examined the images did not know what ailed the patients, but they were aware of being part of a research project, and they were told to search for all possible diseases of the chest region.

From 18 to 89 percent hits

The results were remarkable. By studying the X-ray images, the radiologists found the correct answer in only 18 percent of the cases. In other words, they missed 82 percent of the diagnoses. With ultralow-dose CT, the radiologists made a correct diagnosis in 89 percent of the cases.

“X-rays are taken out of old habit, but with X-ray the cancer is detected too late. It’s therefore smart to use ultralow-dose CT to be able to detect the disease in time,” Aaløkken states.

Moreover, with X-ray images the radiologists detected fifteen times as many false positives. A false positive means that the patient is told that he is ill, even if he is as fit as a fiddle.

“False positives are a burden on the patient. They also entail unnecessary check-ups, which incur a high cost on society,” says Aaløkken, who concludes:

With an X-ray examination, there is a high likelihood that you will not have any answer as to whether you are ill, and an answer that says that you are ill even though you are healthy. Many are diagnosed too late. This is a dramatic consequence of the fact that the health services give priority to X-ray images above CT images.

Their research caused a stir at the world’s largest medical conference for radiology, RSNA, in 2012. Their academic article was nominated as one of the ten best from the conference.

“Even though our results are extremely convincing, we need to undertake a full-scale test to be absolutely certain.”

A question of economics

Before the diagnostic procedure is changed, the researchers must calculate the cost to society.

“A CT machine costs ten times more than an X-ray machine, but it is also costly to treat patients with advanced lung cancer.

Most people believe that X-ray is a quicker procedure than CT. This is not so.

“An X-ray check takes five minutes. A low-dose CT check goes almost as quickly; it takes seven minutes. On the other hand, the radiologists need two to three times longer to interpret a CT image,” Aaløkken and Martinsen underscore.

Odd Terje Brustugun, associate professor at the Department of Oncology at Oslo University Hospital and assistant professor at the Institute of Clinical Medicine, UiO, confirms that Aaløkken and Martinsen are on the right track.

“As far as I have understood, the method can be used on existing, modern CT machines. Before it can replace ordinary chest X-ray some work needs to be done in terms of the resource situation and training of radiographers and radiologists. The method should be tested on a greater number of patients and compared to other techniques on a larger scale before we can conclude how well it works,” Brustugun points out.

“We believe that there is a connection between metabolism, inflammation, heart attack and stroke,” says Bente Halvorsen, professor at the Research Institute for Internal Medicine, University of Oslo, Norway. Together with the research group’s leader, Pål Aukrust, who last year received the university’s research award for his work on inflammatory diseases, and researcher Arne Yndestad, she has looked deeply into the molecular explanation of why overweight is harmful. “With this new knowledge, we can better understand why too much food can cause such serious diseases as heart attack, stroke, cancer and chronic intestinal inflammation.”

We eat too much

Malnutrition and insufficient nutrition lower the immune response, and this increases the risk of infections. If the immune defense system functioned normally, the body would respond with an inflammation to rid itself of the infection. When the immune defense system is impaired, the body is unable to defend itself through inflammation.

Overeating increases the immune response. This increased immune response causes the body to generate excessive inflammation, which may lead to a number of chronic diseases.

“It is therefore important to keep a balance. Too little and too much nutrition may both upset the immune defense system and increase the risk of disease.”

A number of diseases are caused by inflammation. Arthritis is a chronic inflammatory disease. Heart attack is an example of a disease that causes an acute and powerful inflammatory reaction.

“We can reduce the inflammatory reaction by losing weight. Some people risk never getting rid of the inflammation. We have attempted to understand what is needed to reduce the inflammatory reaction without having to lose weight,” Halvorsen explains.

Unfortunately, storage of energy causes an inflammatory reaction. The explanation lies in the close connection between the body’s immune system, energy conversion and the way in which we store energy. It can all be explained in terms of evolution. In our ancestors many hundred million years ago, this was all concentrated in one single organ, like in the modern-day fruit fly. Even though in humans this task is divided among three organs — the fatty tissue that stores energy, the liver that converts energy and the immune system — these organs still communicate closely with each other.

Evolutionarily speaking, humans are not made to eat so much on the contrary; they are intended to toil for their food.

“Mankind’s great challenge has consisted in obtaining sufficient food and surviving infections. Today, we rarely die of infections, but on the other hand we eat too much,” says Arne Yndestad.

Damage to the powerhouse in the cells

The researchers believe that overeating may cause stress to the mitochondria. The mitochondria are the cells’ powerhouses, converting fatty acids to energy.

Evolutionary biologists believe that mitochondria were bacteria that as life has developed have become an integrated part of our cells. The immune system may nevertheless perceive the mitochondria as foreign bodies. Much immunological research therefore focuses on the mitochondria.

When fatty acids accumulate in the cells, the mitochondria become stressed and gradually also damaged.

“When the cells receive excessive energy, the system starts to falter, and the engine may stall. Too much fatty acid causes an oxidative stress in the cells. We believe that long-term stress on the mitochondria may cause metaflammation. A metaflammation is a low-grade chronic inflammation over many years, and unfortunately it’s a condition that’s difficult to detect,” says Yndestad.

The body has its own defense system, called autophagy, which should eliminate damaged mitochondria. When we overeat, free fatty acids accumulate in the cells. This stresses the mitochondria. The stress in the cells causes damage to the mechanism that should eliminate the mitochondria.

When damaged mitochondria accumulate, the immune response is activated. This immune response is exactly what causes the inflammation.

Key signal molecules have been found

The UiO researchers, who also work at the new K.G. Jebsen Inflammation Research Centre, have studied some of the signal molecules inside the cells that trigger the inflammatory reaction. In other words, they have found one element of the energy conversion that may explain what happens when the mitochondria are dealing with the fatty acids. The special element, which is also an enzyme, has previously been studied in stroke patients.

“We believe that this enzyme can be regulated by overnutrition and that it is a key constituent in the inflammatory reaction. We have found that the plaque in the arteries of patients with arteriosclerosis contained a lot of this enzyme. When the plaque bursts, the patient may suffer a stroke,” Halvorsen points out.

In trials with mice, the researchers have tested what happens when the amount of this special enzyme is increased. It reduced the degree of arteriosclerosis.

Strengthening the theory

Their theory was strengthened when they studied how the absence of inflammasomes had an effect on heart function. Inflammasomes are part of the intra-cellular immune defense system.

“When the cells received excessive amounts of fatty acids, the inflammasomes were activated, causing an inflammation.”

Mice with heart attacks functioned better when the inflammasomes were removed.

“So this is about restoring the balance in the immune defense system,” says Yndestad .

A correlation with cancer

The researchers believe that their new discovery may also be a key mechanism in the development of cancer.

“Cancer cells need access to a lot of energy to divide. The cellular stress may transform cells to cancer. Studies of overweight may therefore give us a better understanding of cancer,” Halvorsen explains.

One who is particularly interested in this research is Professor Kristin Austlid Taskén at the Institute for Cancer Research.

“People who are overweight more often develop an aggressive variant of prostate cancer. Although the connection between overweight and cancer is well known, however, little is known about the mechanisms involved” Taskén says.

Her specialty is prostate cancer, a disease that strikes 5000 Norwegians each year.

“Since this is the most common form of cancer among men, it is essential to obtain more knowledge about the way in which overweight affects the metabolism of the cancer cells and leads to aggressive prostate cancer. For the cancer cells to be able to divide rapidly, they make use of new metabolic pathways that are quite unknown to us today. It is therefore useful to have more knowledge that can help us find new drugs that can dispose of the cancer cells,” Taskén points out to the research magazine Apollon.